The clinical utility of the antitumor anthracycline antibiotics adriamycin and daunomycin is strictly limited by their ability to produce severe and often lifethreatening cardiotoxicity. In attempting to explain the basis for this toxicity it has been hypothesized that because of their quinonoid nature these agents enhance the formation of oxygen free radicals (e.g., superoxide ions) which, in turn, cause peroxidation of cardiac lipids and ultimately the observed toxicity. While most tissues contain enzymes that detoxify these highly reactive radicals, the heart is particularly deficient in these protective enzymes. The present proposal postulates that the ability of the anthracyclines to generate these radicals can be reduced, without hindering their antitumor efficacy, by the placement of amino groups on the B and/or D rings of the tetracyclic aglycone. In order to test this hypothesis it is proposed to synthesize a series of hydroxy- and aminoanthraquinonyl glycosides as models in which to develop a relationship between structure, superoxide generation, lipid peroxidation, and possibly cardiac toxicity. The results of such studies can then be used to predict, prior to their actual synthesis, which aminated anthracyclines are least likely to produce cardiotoxicity.